tbuckley/cabot-search huggingface dataset:
A phase II randomized, open-labelled, multicenter study of safety and efficacy of combination brigatinib and carboplatin-pemetrexed therapy or brigatinib monotherapy as first-line treatment in patients with advanced ALK-positive non–small cell lung cancer (IFCT-2101 MASTERPROTOCOL ALK).
Authors: Michaël Duruisseaux, Aurélie Swalduz, Julien Mazieres, Fabrice Barlesi, Elodie Amour, Franck Morin, Virginie Westeel
Journal: Journal of Clinical Oncology (2022)

TPS9144 Background: Second generation ALK tyrosine kinase inhibitors (ALK-TKI), including brigatinib, provide substantial therapeutic benefit in first-line treatment of ALK-positive NSCLC patients (pts) but relapse eventually occurs in all pts due to development of drug resistance, possibly caused by emergence of drug-tolerant cells (DTC). Combining chemotherapy to TKI may prevent DTC emergence in preclinical studies, and results in prolonged progression-free survival (PFS) and overall survival in EGFR-mutant NSCLC. We hypothesize that combination of second generation ALK-TKI with chemotherapy will improve clinical outcomes in advanced ALK-positive NSCLC patients. The IFCT-2101 MASTERPROTOCOL ALK trial will evaluate the efficacy and safety of brigatinib and carboplatin-pemetrexed combination in treatment-naïve metastatic ALK-positive NSCLC. Methods: The IFCT-2101 MASTERPROTOCOL ALK randomized, open-label phase II trial will enrol 110 pts in 30 French centers over 24 months. Eligible pts will have metastatic NSCLC with ALK-fusion according to local testing, be untreated for advanced disease, and have an ECOG Performance Status (PS) of 0-1 and at least one measurable lesion per RECIST 1.1. Pts with asymptomatic and stable brain metastases (BM) will be eligible. Exclusion criteria include leptomeningeal metastases. Patients will be randomized 1:1 to receive brigatinib monotherapy (Arm A) or combination brigatinib and carboplatin-pemetrexed therapy (Arm B), with PS (0 vs 1) and BM (presence vs absence) as stratification factors. Brigatinib will be administered at a dose of 90 mg QD for a 7-day lead-in period followed by 180 mg QD continuously, in 28-day cycles. In Arm B, 4 cycles of carboplatin (AUC 5) and pemetrexed (500 mg/m 2 ) therapy every 3 weeks will be added at Day 8 of brigatinib treatment. Treatment will continue until progression, intolerable toxicity or discontinuation. The first 26 pts enrolled in Arm B will represent the population of a safety phase, during which adverse events (AE) will be closely monitored by an independent data monitoring committee. The primary endpoint is investigator-assessed 12-month PFS rate. Secondary endpoints include independently-reviewed 12-month PFS rate, overall response rate (ORR), 12-month intracranial PFS and ORR, incidence, nature and severity of AEs, and impact of ALK-fusion detection, co-mutations and clearance of circulating tumor (ct) DNA (Guardant360) on outcome. Exploratory objectives include the evaluation of early blood ctDNA decrease on patient outcome. The study is enrolling and primary completion date is March 2025. Clinical trial information: NCT05200481.
BTX-1188, a first-in-class dual degrader of GSPT1 and IKZF1/3, for treatment of acute myeloid leukemia (AML) and solid tumors.
Authors: Aparajita Hoskote Chourasia, Hannah Majeski, Angela Pasis, Paul Erdman, Ashwini Oke, David Hecht, David Lonergan, Frank Mercurio, Kyle Chan, Dung Luong Thai, Leah Fung
Journal: Journal of Clinical Oncology (2022)

7025 Background: BTX-1188 is a first-in-class oral molecular glue that degrades GSPT1 and IKZF1/3 and is currently in phase 1 clinical trials for treatment of hematologic and solid malignancies. Targeted protein degradation of cereblon neosubstrates is clinically validated in the treatment (tx) of hematologic malignancies (Lu 2014, Zou 2020). Methods: Cell viability in BTX-1188-treated cells and patient samples was measured by CellTiter-Glo 2.0 assay (Promega). Substrate degradation and apoptosis profiles were analyzed by immunoblots of protein lysates from cells treated with DMSO or BTX-1188. Vehicle, or 30 or 40 mg/kg IP BTX-1188, was used in athymic nude mice AML xenograft models. Results: BTX-1188 is a rapid, deep, and potent degrader of GSPT1 and IKZF1/3 and inhibitor of Myc in several cancer cell lines (Table). Proteomics and immunoblot analysis of AML cell line, MV-4-11, shows significant degradation of GSPT1 and IKZF1 after 2 h tx with 100 nM BTX-1188 ( P&lt;1x10 -5 ) and 6 h tx with 3 nM BTX-1188 (&gt;90% of GSPT1), respectively, indicating rapid and potent neosubstrate degradation. BTX-1188 also durably degrades GSPT1 where tx with 30 nM for 6 h followed by washout maintains significantly lower levels of GSPT1 and sustained apoptosis for up to 24 h. Owing to IKZF1/3 degradation, BTX-1188 has immunomodulatory properties as seen by inhibition of proinflammatory cytokines (IL-1β, IL-6, TNFα) and induction of IL-2 by LPS and αCD3-stimulated PBMCs, respectively. This approach is expected to improve clinical outcomes and reduce toxicities associated with pure GSPT1 degradation (CC-90009), thus expanding the therapeutic window of BTX-1188. Functionally, BTX-1188 is cytotoxic in various cancer cell lines such as Myc-driven lines (IC 50 range: 0.5-10 nM) and primary human AML patient samples (IC 50 range: 0.4-1.5 nM), including relapsed/refractory-, cytarabine- and venetoclax-resistant samples. The durability of GSPT1 degradation and sustained apoptosis in response to BTX-1188 tx is further reflected in in vivo efficacy models where daily or intermittent dosing of BTX-1188 results in potent and sustained antitumor activity. Conclusions: These preclinical data show that BTX-1188 is a promising drug candidate for AML and other tumor types. Its immunomodulatory properties owing to IKZF1/3 degradation may prevent systemic inflammatory dose-limiting toxicities associated with pure GSPT1 degradation (Uy 2019). BTX-1188 has entered phase 1 clinical studies for advanced solid tumors and AML. DC 50 (nM) or inhibitory concentration (nM) of BTX-1188 at 6 h of Tx. [Table: see text]
Partner and localizer of BRCA2 (PALB2) pathogenic variants and ovarian cancer: A systematic review and meta-analysis.
Authors: Priyanka Narayan, Muhammad Danyal Ahsan, Shanice Beaumont, Jenny Lin, Luiza Perez, Leslie Bull, Isabel Wolfe, Andy Hickner, Eloise Chapman-Davis, Evelyn Cantillo, Kevin Holcomb, Ravi Sharaf, Melissa Kristen Frey
Journal: Journal of Clinical Oncology (2022)

e17597 Background: Approximately 20% of ovarian cancers are due to an underlying germline pathogenic variant. While several genes have been well-established in the development of hereditary ovarian cancer (e.g. BRCA1/2, RAD51C, RAD51D, BRIP1, mismatch repair genes), there are other genes for which the cancer risk is less certain and management recommendations remain controversial, including partner and localizer of BRCA 2 (PALB2). We sought to evaluate the association between PALB2 germline pathogenic mutations and ovarian cancer in the first meta-analysis on this topic. Methods: We conducted a systematic review and meta-analysis in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PROSPERO no.: CRD42021281325). We searched key electronic databases to identify studies evaluating multigene panel testing in patients with ovarian cancer. Eligible trials were subjected to meta-analysis. Results: Thirty-seven studies met inclusion criteria. We found 55,137 cases of ovarian cancer with information available on germline PALB2 pathogenic variant status. Reported histological subtypes included serous adenocarcinoma (74.8%), endometroid (6.5%), clear cell (2.1%), mucinous (3.1%), and other (13.5%). Most ovarian cancers were stages III (73.5%) and IV (22.3%), followed by II (6.0%), and I (4.1%). Among ovarian cancer cases with PALB2 sequencing data available, 0.4% demonstrated a germline pathogenic variant in the PALB2 gene and the pooled odds ratio (OR) for having a PALB2 mutation was 2.31 (95% CI 0.89- 5.98). Among 94 patients with a germline PALB2 pathogenic variant, the pooled odds ratio (OR) for developing ovarian cancer was 2.85 (95% CI 1.58-5.15) relative to 33,855 patients without PALB2 mutations. Conclusions: Our meta-analysis demonstrates that the pooled OR for developing ovarian cancer with an underlying PALB2 germline pathogenic variant was 2.85 (95% CI 1.58-5.15). While this risk is lower than many of the well-established hereditary ovarian cancer genes, it does exceed the baseline population risk of 1-2%. Whether this meets the threshold to consider risk-reducing salpingo-oophorectomy is up for debate. Large population-based studies and evaluation of the combination of PALB2 mutations and cancer family history are needed to improve management recommendations for patients harboring pathogenic mutations in this gene.
Prognostic factors of stage I endometrioid or clear cell or mucinous ovarian cancer: Analysis based on surveillance, epidemiology, and end result program, 2000-2016.
Authors: Jing Li, Zhongqiu Lin, Huimin Qiao, Lijuan Wang, Yunyun Liu, Huaiwu Lu
Journal: Journal of Clinical Oncology (2022)

e17589 Background: Endometrioid (EEOC), clear cell (OCCC) or mucinous ovarian cancer (MOC) had the highest incidence of Less Common Ovarian Cancers (LCOC). The benefit of adjuvant chemotherapy, lymphadenectomy or fertility-sparing surgery (FSS) for Stage I of these rare cancers remains unclear. Methods: We conducted a retrospective case-controlled study examining the Surveillance, Epidemiology, and End Result (SEER) database between 2000 and 2016. Propensity score matching is used to avoid the selection bias caused by the heterogeneity of demographic and clinical characteristics. Adjuvant chemotherapy or lymphadenectomy or fertility-sparing surgery on overall survival (OS) was compared with log-rank tests. A univariate and multivariate Cox analysis was performed to control for confounders. A nomogram was developed and the discriminatory ability of the model was analyzed. Results: The study identified 4,681 patients with FIGO stage I EEOC, 2,450 with stage I OCCC, and 2,839 with stage I MOC. After the propensity score matching, there was an equally comparable number of patients with or without adjuvant chemotherapy. The results showed that adjuvant chemotherapy could not prolong the 5-year OS of patients with stage I OCCC (86.7% vs. 85.9%, p = 0.732) and MOC (87.6% vs. 88.2%, p = 0.843). Adjuvant chemotherapy was associated with a 5-year OS benefit only in the subgroup of patients with substage IC, grade 3 EEOC (85.2% vs. 67.7%, p = 0.008). We also found that lymphadenectomy improved the 5-year OS of stage I EEOC (93.5% vs. 86.3%, P = 0.000), OCCC (87.8% vs. 82.8%, P = 0.040) and MOC patients (91.8% vs. 84.2%, P = 0.000). Furthermore, we observed that the 5-year OS raised in stage I EEOC (91.9%vs. 87.7%, P = 0.029) and OCCC (87.6% vs. 81.3%, P = 0.051) patients when conducted the non-fertility-sparing surgery (non-FSS) rather than the FSS. However, FSS did not significantly impact the 5-year OS of MOC patients (91.3% vs. 88.8%, P = 0.181). The nomogram survival prediction model showed that the area under the receiver operating characteristic (ROC) curve (AUC) was 0.650, 0.640 and 0.710 in EEOC, OCCC and MOC, respectively. The C-indexes for the OS were 0.666 (95%CI:0.638-0.694), 0.613 (95% CI:0.575-0.650) and 0.677 (95% CI:0.637-0.716), respectively. Conclusions: Adjuvant chemotherapy was associated with a 5-year OS benefit for patients with stage IC, grade 3 EEOC, but it was unnecessary for patients with stage I OCCC and MOC. Lymphadenectomy was associated with a survival benefit for these early cancer patients. FSS is appropriate for stage I MOC but needs to be discussed for stage I EEOC and OCCC. We constructed predictive nomograms to evaluate the OS of patients with stage I EEOC, OCCC or MOC, and it will provide an individualized evaluation of OS for suitable treatments.
Do publicly available OncoGenomic databases represent the population? A comparative analysis.
Authors: Danielle Brazel, Priyanka Kumar, David Joseph Benjamin, Justin Tyler Moyers
Journal: Journal of Clinical Oncology (2022)

6588 Background: Large publicly available databases are important repositories for analyses of clinicogenomic research used for identifying clinically relevant biomarkers. Diversity among individuals in these repositories is key for ensuring applicability of findings to patient populations. Methods: We compared two publicly available pancancer databases from academic institutions: The Cancer Genome Atlas (TCGA) and United States (US) institutions from the American Association for Cancer Research (AACR) Project GENIE version 11.0 (APG) with cancer incidence statistics from The US Cancer Statistics (USCS) in 2018, the most recently available data. We compared demographic data from key individual cancer types (Lung, Colorectal, Prostate, Breast, Gliomas, and Leukemias) for gender, race, and ethnicity. Frequencies are displayed as percentages and compared by Chi-Squared method. Results: The USCS includes 1,708,921 new cases in 2018 while the TCGA includes 12,958 cases and APG includes 109,041 cases. Women account for 49.5% of all cancer diagnosis and similarly 50.4% of all cases in AACR and 51.2% of TCGA cases. Table summarizes key demographic differences. Amongst all cancer types, 78% of all US cancers occur in White patients however 84% and 83% of patients were White in AACR and TCGA respectively. 16% of prostate cancer cases occur in Black patients, but only 9% (n = 328/3993) of AACR and 11% (n = 51/484) of TCGA cases were Black (p &lt; 0.01). However, while Black patients are only 2% of all breast cancer diagnoses, they accounted for 9% (n = 841/9871) of AACR and 16% (n = 203/1343) of TCGA cases p &lt; 0.01). Patients of Hispanic ethnicity were underrepresented amongst the population and all single tumor types with Hispanics accounting for 8% of cases in USCS but only 5% in the AACR and TCGA (p &lt; 0.01). Pancreatic and lung cancers, which have historically short survivals, both had lower median ages at sequencing compared to the median age of diagnosis. Median age of sequencing for pancreatic cancers was 65 in both TCGA and AACR, while median age at diagnosis in US is 70. Median age at diagnosis of lung cancers is 71 years in US, however median age was 67 in both AACR and TCGA. Conclusions: Patients with advanced age and minority races are underrepresented in publicly available American databases. To make informed analyses from genomic databases, the diversity of the population must be reflected in these databases and efforts must be made to increase representation of underrepresented groups. [Table: see text]
POSTCare-O: A survivorship care transition for women with ovarian cancer.
Authors: Elizabeth Ann Kvale, Farya Phillips
Journal: Journal of Clinical Oncology (2022)

e17583 Background: The POSTCare survivorship care transition is efficacious as a quality-of-life intervention for patients diagnosed with breast cancer but has not been studied in women with ovarian cancer. Ovarian cancer patients who complete treatment face unprecedented uncertainty regarding survivorship including life expectancy, and the balance of healthcare demands with living well. The routine provision of automated survivorship care plans (SCPs) by advanced practice providers (APPs) is a standardized approach which does not consider the unique needs of ovarian cancer survivors. Aim: To adapt the POSTCare intervention for ovary cancer patients by incorporating a component of concurrent palliative care and tailoring the skills of an existing workforce. Methods: We provided web-based training to APPs from Gyn Oncology programs. Qualitative methods explored the POSTCare protocol, ideas for adapting the intervention, and training preferences. We conducted semi-structured interviews with nurses who completed the POSTCare-O web-based training and utilized components of the POSTCare model in clinical care. The goal was to discover the elements of the model that worked well in their setting, which elements they can utilize routinely to meet the needs of patients, and which elements they find most satisfying. Results: Nine advanced practice providers completed online training and follow up assessment. All participants passed the final competency assessment (role play skills check). Exit interview data revealed four areas where participants reported changes in their own perceptions and skills related to survivorship care that they attributed to the POSTCare-O training program. APPs reported the training increased their competency in palliative care skills and left them better able to support survivors in the face of uncertainty. Specifically, the training; (1) enhanced their communication skills; (2) developed their understanding of survivorship care as more than just surveillance; and (3) demonstrated how to implement patient driven goal setting. Conclusions: POSTCare intervention can serve as a platform for delivery of components of early concurrent palliative care that is acceptable to ovarian cancer patients who remain focused on life-prolonging treatments. POSTCare-O web based training improved APPs appreciation of the scope of survivorship care beyond just surveillance and management of physical effects. This training provided the tools necessary for clinicians to provide whole person care while implementing patient driven survivorship care planning.
Midostaurin in advanced systemic mastocytosis: A systematic review and meta-analysis.
Authors: Ziad Abuhelwa, Azizullah Beran, Navkirat Kahlon, Wasef Sayeh, Waleed Khokher, Ragheb Assaly, Danae M. Hamouda
Journal: Journal of Clinical Oncology (2022)

e19084 Background: Midostaurin, an oral multikinase inhibitor including inhibition of KIT D816V, is approved for the treatment of advanced systemic mastocytosis (SM). Few studies have investigated the use of midostaurin in patients with advanced SM, but the data on its efficacy and safety in this population remains limited and uncertain. Therefore, we conducted this systematic review and meta-analysis to better assess the efficacy and safety of midostaurin in advanced SM. Methods: We systematically searched the following databases: PubMed/MEDLINE, Embase, and Cochrane through February 02, 2022, to include all studies that assessed the effect of midostaurin on clinical outcomes of patients with advanced SM. Our primary outcome was the overall response rate (ORR). The secondary outcomes included the rates of progressive disease (PD), stable disease (SD), and treatment discontinuation due to adverse events (AEs). All statistical analyses were performed using Open Meta Analyst (CEBM, University of Oxford). Pooled rates and corresponding 95% confidence intervals (CI) were calculated using DerSimonian-Laird/Random-effects approach. Results: Four studies (two clinical trials and two observational studies) with a total of 156 patients with advanced SM were included in the pooled analysis. The mean age of the patients was 59.6±15.8 years, and males represented 64.7% of total patients. The most common subtype of advanced SM was SM associated with hematological neoplasm (59%) followed by aggressive SM (23.1%). Three studies reported the KIT D816V mutation status, and 85.2% of patients were positive for KIT D816V mutation. The mean duration of treatment with midostaurin was 10±15.3 months. The pooled ORR was 60% (95% CI 46.5%-73.5%) over a mean follow-up duration of 41.1±38.7 months. The PD and SD rates were 12.8% (95% CI 7.6%-18%) and 10.6% (5.3%-15.9%), respectively. Treatment discontinuation due to AEs occurred in 25.6% (95% CI 18.8%-32.4%). The most common hematological grade ≥3 treatment-related AE was anemia (29%), while fatigue (7.1%) was the most common non-hematological grade ≥3 treatment-related AE. Conclusions: Our study demonstrated that midostaurin is very effective in patients with advanced SM with an acceptable safety profile. Our meta-analysis is hampered by a limited number of studies, a small sample size, and a lack of a control group. Future large-scale comparative studies are warranted to evaluate the efficacy and safety of midostaurin in these patients.
ALTER-UC-001: Phase II trial of anlotinib plus everolimus as first-line treatment for advanced non–clear cell renal cell carcinoma.
Authors: Hailiang Zhang, Ding-Wei Ye
Journal: Journal of Clinical Oncology (2022)

TPS4598 Background: For patients (pts) with recurrent or stage IV non-clear cell renal cancer (nccRCC), the medical treatment guidelines recommend the first choice to participate in clinical trials, or use TKI drugs such as sunitinib, and mTOR inhibitors such as everolimus. Anlotinib is a novel multi-target tyrosine kinase inhibitor (TKI). It’s antitumor targets include vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptor (PDGFR) and c-kit. This a single-center, single-arm, phase II trial which will evaluate the efficacy and tolerability of anlotinib hydrochloride plus everolimus as first-line therapy in pts with nccRCC (NCT05124431). Methods: Key inclusion criteria are: age ≥18 years; histologically confirmed advanced nccRCC, advanced disease is defined as TNM stage IV, not available for surgery, locally recurrent or metastatic renal cell carcinoma; no prior systemic drug therapy for advanced disease; Eastern Cooperative Oncology Group (ECOG) performance status 0-1. Approximately 30 pts will be assigned to receive anlotinib hydrochloride: 12 mg every 21 days (14 days on treatment from Day 1-14, 7 days off treatment from Day 15-21) by oral, and everolimus 5mg qd, continued for up to 1 year (∼17 cycles ) or until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was objective response rate (ORR). Radiographic imaging will be performed every 6 weeks. Secondary endpoints included overall disease control rate (DCR), progression free survival (PFS), and over survival (OS). Adverse events will be monitored throughout the study and graded according to CTCAE V5.0. Recruitment have begun in Jan. 2022. Research Sponsor: Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Clinical trial information: NCT05124431.